title: Complex regulation of autophagy in cancer - integrated approaches to discover the networks that hold a double-edged sword.
abstract: Autophagy, a highly regulated self-degradation process of eukaryotic cells, is a context-dependent tumor-suppressing mechanism that can also promote tumor cell survival upon stress and treatment resistance. Because of this ambiguity, autophagy is considered as a double-edged sword in oncology, making anti-cancer therapeutic approaches highly challenging. In this review, we present how systems-level knowledge on autophagy regulation can help to develop new strategies and efficiently select novel anti-cancer drug targets. We focus on the protein interactors and transcriptional/post-transcriptional regulators of autophagy as the protein and regulatory networks significantly influence the activity of core autophagy proteins during tumor progression. We list several network resources to identify interactors and regulators of autophagy proteins. As in silico analysis of such networks often necessitates experimental validation, we briefly summarize tractable model organisms to examine the role of autophagy in cancer. We also discuss fluorescence techniques for high-throughput monitoring of autophagy in humans. Finally, the challenges of pharmacological modulation of autophagy are reviewed. We suggest network-based concepts to overcome these difficulties. We point out that a context-dependent modulation of autophagy would be favored in anti-cancer therapy, where autophagy is stimulated in normal cells, while inhibited only in stressed cancer cells. To achieve this goal, we introduce the concept of regulo-network drugs targeting specific transcription factors or miRNA families identified with network analysis. The effect of regulo-network drugs propagates indirectly through transcriptional or post-transcriptional regulation of autophagy proteins, and, as a multi-directional intervention tool, they can both activate and inhibit specific proteins in the same time. The future identification and validation of such regulo-network drug targets may serve as novel intervention points, where autophagy can be effectively modulated in cancer therapy.
authors.affiliation: Department of Genetics, Eötvös Loránd University, Pázmány P. s. 1C, H-1117 Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Kubisch
authors.forename: Dénes
authors.initials: D
authors.lastname: Türei
authors.forename: László
authors.initials: L
authors.lastname: Földvári-Nagy
authors.forename: Zsuzsanna A
authors.initials: ZA
authors.lastname: Dunai
authors.forename: Lilian
authors.initials: L
authors.lastname: Zsákai
authors.forename: Máté
authors.initials: M
authors.lastname: Varga
authors.forename: Tibor
authors.initials: T
authors.lastname: Vellai
authors.forename: Péter
authors.initials: P
authors.lastname: Csermely
authors.forename: Tamás
authors.initials: T
authors.lastname: Korcsmáros
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents
keywords: Autophagy; Cancer; ERK; FoxO1/3; GSK3; HIF; IGF; IRE1; JNK; Multi-target drug design; NF-κB; NRF2; Network; PKA; RAS; Regulation; SREBP; TFEB; TGF-β; TP53 tumor suppressor protein; WNT; c-Jun N-terminal kinase; extracellular signal regulated protein kinase; forkhead family transcription factor; glycogen synthase kinase-3; hypoxia-inducible factor; inositol-requiring protein 1; insulin-like growth factor; nuclear factor erythroid 2-related factor 2; nuclear factor kappa beta; p53; protein kinase A; small GTPase protein; sterol regulatory element-binding protein; transcription factor EB; transforming growth factor beta; wingless and int-like protein